Advances in Continuous Renal Replacement Therapy

CSM 2011Dr Anne Leung17th May 2011

Overview

DOSE

Fluid and anticoagulatio

n

Timing of initiation

Membrane

To begin the “Dosing” story of CRRT….

20mL/Kg/hr 35mL/Kg/hr 45mL/Kg/hr

15-days Survival

41% 57% 58% Lancet 2000

Higher the dose the better

EIHF vs Conventional 45mL/Kg/hr for 6 hours then 20mL/Kg/hr vs 20mL/Kg/hr

28-day Survival: 55% vs 27.5%

Piccinni ICM 2006

CVVHDF: more may not be better

PRCT

Single Center

N=200

Pre-dilution

CVVHDF: 20mL/Kg/HrCVVDHF: 35mL/Kg/Hr

Tolwani et al JASN 2008

Intense Conventional

Hemodynamic stable

IHD /SLED 6x/week with Kt/V of 1.2-1.4

IHD /SLED 3x/week with Kt/V of 1.2-1.4

Hemodynamic unstable

CVVHDF 35mL/Kg/Hr

CVVHDF 20mL/Kg/Hr

Intensive RRT = Equal ATN trial

PRCT

N=1124

60 days mortalityIntensive: 53.6%

Less Intensive: 51.5%

What Dose ?

• Before the ATN trial• CRRT: 35mL/Kg/Hr• Daily iHD

• After the ATN trial• SOFA 0-2: 3x/week iHD (Kt/V 1.2)• SOFA 3-4: CRRT 20 mL/Kg/hr or SLED 3x/week• But beware for the need for extra treatment!

Randomized(Post-dilution CVVH)

1508

Low dose(25ml/Kg/hr)

761

High dose(40ml/Kg/hr)

747

Lost to follow up = 1Consent withdrawn = 2

Consent not obtained = 23

Analyzed722

Lost to follow-up = 0Consent withdrawn = 2

Consent not obtained = 16

Analyzed743

RENAL Study

High Intensity

Low Intensity

90-days mortality 44.7% 44.7%

28-days mortality 38.5% 36.5%

Conclusion• Intensity of RRT DOES matter

• Beyond the threshold dose ( 25ml/kg/hr), increasing intensity does not provide further clinical benefit

• Be-aware of the difference between prescribed and delivered dose of RRT• ATN study: 89% -95% • RENAL study: 84-88%

• Minimize the interruption of the treatment time

IVOIRE (hIgh Volume in Intensive Care)—French Study• Inclusion criteria: Septic shock <24 hrs and RIFLE

criteria of injury or worse

• Intervention: High volume (70ml/kg/hr) vs Standard (35ml/Kg/hr) for 96 hours

• Patient number: total of 460 patients

• Primary outcome: 28-day mortality

• Study period: 3 years and completed by Oct 2010

INITIATION OF THERAPY

RIFLE Criteria

Currr Opin Crit Care 8: 509-514 (2002)

Level of injury

Outcome measure

s

From RIFLE to AKINSerum

Creatinine

Increase SCr ≥24.6mmol/L

2-3 folds

Stage 1

Stage 2

Stage 3

The Acute Kidney Injury Network Classification ( AKIN)

Crti Care 11:R31 (2007)

Biomarkers of AKI

uNGAL Serum Cystatin C

MEMBRANE OF FILTER

Super High-Flux or High Cut-ff Membranes

Achieve greater clearance of inflammatory cytokines

- Superior elimination of IL-6- Decrease need of Nor-

adrenaline over time

P.

20

SepteX—High Cut Off Membrane

Pilot Randomized Controlled Study Comparing the Effect of High Cut-off Point Hemofiltration with Standard Hemofiltration in Patient with Acute Renal Failure• Study Population:

• Critically ill patient with AKI and shock that require Nor-adrenaline

• Intervention: • Standard polyamide high flux membrane vs High cut-off

polyamide membrane (P2SH)• CVVH: Qb: 200ml/min, UF of 25ml/Kg/hr

• Size of the study: • 72 patients

• Primary measures• NA-free time in first week after randomization

• Status: • start in Jun 2009 and still recruiting

P.

22

Early Use of Polymyxin B Hemoperfusion in Abdominal Septic Shock--The EUPHAS Randomized controlled Trial JAMA 2009

Polymyxin B immobilized fiberDirect Hemo-Perfusion

Early Use of Polymyxin B Hemoperfusion in Abdominal sepsis

Decrease vasopressor requirement

Better BP and low SOFA score

Mortality of 32 % vs 53%

FLUID & ANTICOAGULANT

Continuous renal replacement therapy: B.E.S.T. Kidney (The Beginning and Ending Supportive Therapy for the kidney).

a worldwide practice survey. 23 Countries, 54 ICUs, 1006 patients with ARF on CRRT

UFH43%

No anticoagulant33%

Citrate10%

LMWH4%

Nafamostat6%

Others4%

Intensive Care Med. 2007;33(9):1563-70

Less clotting in Hollow Fibers membrane Kid Int 1999

Commercial preparation of citrate

solution—Morgera S. et al .CCM 2009

Gp 1 (60Kg)

Gp 2 (60-90Kg)

Gp 3 (>90Kg)

Patient No 19 97 45Blood flow(mL/min)

80 100 120

Dialysate flow (mL/hr)

1500 2000 2500

Citrate flow( mL/hr)

140 170 205

A safe citrate anticoagulation protocol with variable treatment efficacy and excellent control of the acid-base status—CCM 2009

• Result• Median filter time of

61.5 hrs• 5% had filter clot• Excellent control of

acid-base and electrolyte

Use of citrate CVVH was safer and reduced mortality Oudemans MH et al CCM 37:545-552 ( 2009)

Hospital mortality 41 vs 57% (p=0.03)3-month Mortality 45 vs 62% (p=0.02)

CCM 37: 545 - 552 ( 2009)

Surgical

Sepsis Higher SOFA Younger than 73

Negative Fluid Balance Predicts Survival in Patients with Septic Shock--Alsous F. et al Chest 2000

3 5 6 72 41

Net negative fluid balance within first

3 days in ICU

100% 20%

The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock— Murphy CB et al Chest 2009

3 5 6 72 41

20ml/Kg with CVP≥8 within 4 hrs after

vasopressorsNeutral or negative fluid for 2 consecutive days during

first 7 days

Hospital mortality of

18.3%

The Importance of Fluid Management in Acute Lung Injury Secondary to Septic Shock— Murphy CB et al Chest 2009

3 5 6 72 41

20ml/Kg with CVP≥8 within 4 hrs after

vasopressorsNeutral or negative fluid for 2 consecutive days during

first 7 days

Hospital mortality of 77.1%

3 5 6 72 41

Survivor:Fluid balance non-positive

by D4

Sepsis in European Intensive Care Units: Results of the SOFA study— JL Vincent et al 2006;344-353

3 5 6 72 41

Cumulative fluid balance within 72 hrs after onset of

sepsis was independent predictor of

mortality

10% increase in mortality with each 1L increase in cumulative fluid balance

Comparison of Two Fluid-Management Strategies in Acute Lung Injury— NEJM 2006

3 5 6 72 41

Conservative fluid mx

-higher ventilator-free and ICU free days

-Less cardiovascular failure

-Less on dialysisConservative group: zero balance by D4

Fluid Accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury— (PICARD study)Bouchard J et al KI 2009id removal

Fluid overload patient tended to be sicker patient

No Fluid overload

Fluid overload

APACHE III score

79 90

SOFA score 6.7 8.7No of organ failure

2.6 3.2

Resp failure 55% 86%On ventilator

32% 65%

Sepsis/Septic shock

22% 39%

For each weight change class, fluid overload is independent predictor of

mortality

? “Fluid” as the AKI biomarker

USE OF RCA IN QEH ICU

If I find 10,000 ways something won't work, I haven't failed. I am not discouraged, because every wrong attempt discarded is often a step forward....Thomas Edison

Citrate doseCitric Acid

mmol/L

Sodium Citrate

mmol/L

Complementary solution Therapy BFRmL/min

Citrate dose(mmol/L blood)

Country

Apsner 5 10 - CVVH 100 3.7 Austria

Dorval / Leblanc 5 15 Dia: 0.9% Saline (if needed) CVVH(DF) 125 3.7 Canada

Niles - 13.3 - CVVH 180 2.0 USA

Gabutti - 13.3 Dialysate same as citrate CVVH(DF) 125 2.66 Switzerland

Tolwani - 2% 0.9% Saline CVVHD 150 2.0 USA

Sramek - 2.2% Na=120, Bicar=22 CVVHDF 100 3.6 - 6.3 Czech Republic

Bunchman ACD-A Dia: Normocarb CVVHD(F) 150 2.8 USA

Chadha ACD-A Pre: Na=140, Bicar=20 CVVH 50 - 150 1.9 - 4.2 USA

Mitchell / Heemann ACD-A Calcium in dialysate CVVHD 75 5.7 - 8.5 Germany

Gupta ACD-A Calcium in dialysate CVVHDF 150 1.9 USA

Cointault ACD-A Calcium in dialysate & pre CVVHDF 125 3.9 France

Kustogiannis / Gibney - 3.9% Dia: Na=110, Bicar=variable CVVHDF 125 3.6 Canada

Mehta - 4% Dia: Na=117, Bicar=0 CVVHD(F) 100 3.7 - 5.9 USA

Hoffmann - 4% Pre: 0.9% Saline CVVH 125 3.1 USA

Monchi - 1000 Post: Na=120 , Bicar=0 CVVH 150 4.3 France

Evenepoel - 1035 Calcium in dialysate IHD 300 4.3 Belgium

Who can do that ?

PYNEH ICU (1995-2003)

AK 10 machine

Non-integrated approach

Ci-Ca Dialysate solution

Solution for RCA--Gambro

PYNEH ICU ( 2004 …..

RCA CRRT—QEH Regime

RCA CRRT—QEH Regime

RCA CRRT—QEH Regime

CaCl2 infusion

Summary of the regime• Machine: Prismaflex

• Pre-dilution with Primocitrate 10/2 at rate of 2500mL/hr

• Blood flow at 150ml/min

• Both UF and blood flow rate fixed

• Separate infusion of NaHCO3 ( initial 50ml/hr for 2 hr then 30ml/hr ) and Calcium chloride infusion via CVC at 6 ml/hr

• For fluid removal= desired fluid removal + flowrate of NaHCO3

• Measure Na, K, BE, ABG and ionized calcium Q4-6 hr

• Target ionized calcium 0.9 – 1.3 mmol/L

Implementation• Theory Session

• For both nurses and doctors

• Practical Session• By Gambro in early March

• Guideline as the reference

• Case selection• Avoid those with liver dysfunction, after massive transfusion and

severe metabolic acidosis with pH<7.1• Start with post-op case with mild to moderate acidosis and fluid

problems• Start during the daytime• Gambro technical support stand-by during the initial phase

• Trouble shooting• Contact Dr Anne Leung

• Mechanism of action

• Exclusion criteria

• Set up of the citrate circuit

• Monitoring during RCA

• Titration of electrolyte and acid-base

• Citrate toxicity

7th Jul 2010

Demographic data

Reasons for admission for CRRT

How long the circuit last?

Mean duration ( hr) 31.4±14.4

Maximum duration( hr) 62.3

Minimum duration ( hr) 5.2

Circuit time

Number of episode

Percentage

24 hrs 23 41%

>24% 33 59%

>48% 9 16%

Reasons for termination CRRT

Last from 22 to 49.5 hrs

-5 due to procedures-3 due to nursing manpower restrain

Electrolyte disturbance during Citrate CVVH

Only 2 patients had citrate accumulation

Only 2 patients with Total Ca/iCa >2.5

had citrate accumulation

Rate of correction of metabolic acidosis

Median BE o f-4.5 and it took 20 hrs to reach the median BE of 0

Cases of citrate accumulation　 Circuit

time(hr)Base Excess changes over time

Anion Gap

Total Ca/iC

a

Bil(start)

　 　 Baseline BE 4hrs 8 hrs 12 hrs 16 hrs 20 hrs 24 hrs 　 　 　Case 1 9.6 -12 -6 -8 -10 　 　 　 29 4.1 27

Case 2 24 -3 -5 -3 -3 -5 -4 -1.2 27 2.87 61

Case 3 9.8 -17 -15 -16 　 　 　 　 32 2.4 54

Case 4 25 -14 -11 -11 -13 -15 　 　 36 2.46 5

Onset:10 to 25 hours after commencement of therapy

Lab data suggesting citrate accumulation: slow correction of metabolic acidosis or worsening of control of metabolic acidosis Confirmation:Increased anion gap;High Total Ca/iCa >2.5 and Spontaneous correction of metabolic acidosis after stopping the therapy

ICU and Hospital outcome

ICU mortality of 23% Hospital mortality of 54.5%

"Genius is one per cent inspiration and ninety-nine per cent perspiration. Accordingly, a  'genius' is often merely a talented person who has done all of his or her homework."  

--Thomas Edison